Antibody Generation of ROS and Macular Degeneration

ROS 和黄斑变性的抗体生成

• 批准号: 7096710
• 负责人: PAUL WENTWORTH
• 金额: $ 27.89万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096710
• 关键词: antibody; culture; human; immunoglobulins; lighting; macular degeneration; oxidative stress; singlet oxygen

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of blind registration in the developing world and yet its pathogenesis remains poorly understood. However, there is increasing evidence to support a role for the immune system and oxidative stress, arising from an imbalance in the production and destruction of reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide and singlet oxygen, in disease progression. There is also clear evidence that photochemical sensitization of chromophores stored within lipofuscin in the retinal pigment epithelial (RPE) cells via absorption of both ultraviolet and visible light, leads to ROS generation and damage in the ageing eye. We have recently shown that all antibody molecules, regardless of species or antigenic determinant, have an intrinsic ability to generate a cascade of potent oxidants when presented with either a chemical or photochemical source of singlet dioxygen. The end product of the antibody-catalyzed water-oxidation pathway (ACWOP) is hydrogen peroxide and thus the implication for this pathway to play a role in AMD via interception of photochemically generated singlet oxygen is a real possibility and would lead to an increase in overall oxidative stress. We intend to investigate this hypothesis with the three following specific aims: 1. Specific Aim #1 To determine whether oxidants generated by the ACWOP, are damaging to passaged human RPE cells or primary cultured human RPE cells, in terms of cytotoxicity, apoptosis and expression of heat shock protein (Hsp) 27. 2. Specific Aim #2 To determine whether the ACWOP can be activated by photoirradiation of A2E-loaded RPE cells and whether such activation enhances photochemical damage to these passaged and primary cultures of human RPE cells. 3. Specific Aim #3 To determine whether the ACWOP when activated in whole blood, plasma and serum can affect RPE cell survival

描述（由申请人提供）：与年龄相关的黄斑变性（AMD）是发展中国家盲目登记的主要原因，但其发病机理仍然很少了解。然而，越来越多的证据支持免疫系统的作用和氧化应激，这是由于反应性氧（ROS）的产生和破坏，例如超氧化物阴离子，过氧化氢和单线氧在疾病进展中。还有明确的证据表明，通过吸收紫外线和可见光，在视网膜色素上皮（RPE）细胞中储存的发色团的光化学敏化，可导致衰老眼的ROS产生和损害。我们最近表明，无论物种或抗原决定因素如何，所有抗体分子都具有固有的能力，可以产生一系列有效的氧化剂，当时用化学或光化学的单粒二氧化物来源出现。抗体催化的水氧化途径（ACWOP）的最终产物是过氧化氢，因此，通过拦截光化学生成的单线氧在AMD中发挥作用的意义是真正的可能性，并导致总体上增加氧化应激。我们打算用以下三个特定目的来研究这一假设：1。特定目的1，以确定ACWOP产生的氧化剂是否会在细胞毒性，凋亡和表达上损害传递的人RPE细胞或原发性培养的人RPE细胞。热休克蛋白（HSP）27。2。具体目的＃2，以确定ACWOP是否可以通过A2E负载的RPE细胞的光辐射激活ACWOP，以及这种激活是否会增强对这些传递的人类RPE细胞和原发性培养的光化学损害。 3。特定的目标＃3确定在全血，血浆和血清中激活的ACWOP是否会影响RPE细胞存活